Facile One-Pot Synthesis of Substituted Hydantoins from Carbamates

Article abstract of DOI:10.1055/s-0036-1588468

A novel and simple approach for the preparation of 3-substituted, 5-substituted, or 3,5-disubstituted hydantoins is reported. It involves the reaction of α-amino methyl ester hydrochlorides with carbamates to yield the corresponding ureido derivatives, which subsequently cyclize under basic conditions to produce substituted hydantoins in good yields. By applying this method, the bioactive anticonvulsant drug ethotoin was synthesized in good yield. The process avoids conventional multistep protocols and does not use the hazardous, irritant, toxic, or moisture-sensitive reagents, such as isocyanates or chloroformates, that are commonly used for the synthesis of these important compounds.

Full text of DOI:10.1055/s-0036-1588468

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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A
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D. K. Tanwar et al.
Letter
Synlett
Facile One-Pot Synthesis of Substituted Hydantoins from Carba-
mates
O
Dinesh Kumar Tanwar
H
O
i) MeCN–Et3N
(2:1), reflux, 10 h
O
N
R1
HN
R1
R2
Anjali Ratan
O
N
R2
O
Manjinder Singh Gill*
NH2⋅HCl
ii) NaOH (2.5 equiv), reflux, 8 h
O
R1 = H, alkyl, phenyl and benzyl
R2 = H, alkyl and aralkyl
Department of Pharmaceutical Technology
(Process Chemistry), National Institute of
Pharmaceutical Education and Research
(NIPER), S.A.S. Nagar, Punjab-160062, India
msingh@niper.ac.in
3-substituted,
5-substituted and
3,5-disubstituted hydantoins
23 examples
65–77%
Received: 13.04.2017
Accepted after revision: 21.05.2017
Published online: 03.08.2017
also used as catalysts in organic transformations.18 Further-
more, 1,3-dibromo-5,5-dimethylhydantoin is used as a re-
agent in bromination reactions.19
DOI: 10.1055/s-0036-1588468; Art ID: st-2017-d0256-l
O
Abstract A novel and simple approach for the preparation of 3-substi-
tuted, 5-substituted, or 3,5-disubstituted hydantoins is reported. It in-
volves the reaction of α-amino methyl ester hydrochlorides with carba-
mates to yield the corresponding ureido derivatives, which
subsequently cyclize under basic conditions to produce substituted
hydantoins in good yields. By applying this method, the bioactive anti-
convulsant drug ethotoin was synthesized in good yield. The process
avoids conventional multistep protocols and does not use the hazard-
ous, irritant, toxic, or moisture-sensitive reagents, such as isocyanates
or chloroformates, that are commonly used for the synthesis of these
important compounds.
O
N
O
CF3
NO2
HN
NH
HN
HN
N
O
O
O
Nilutamide
Ethotoin
Phenytoin
HO
O
CN
CF3
N
N
Key words hydantoins, aminocarboxylate hydrochlorides, carba-
O
mates, ureido compounds, ethotoin, medicinal chemistry
RU58841
Figure 1 Biologically active substituted hydantoins
Hydantoins (imidazolidine-2,4-diones) are an import-
ant class of compounds in medicinal chemistry due to their
numerous therapeutic applications (Figure 1).1 The hydan-
toin scaffold is an important structural component of vari-
ous valuable pharmaceuticals, such as antiepileptics (phe-
nytoin and ethotoin),2 antiarrhythmics (azimilide),3 skeletal
muscle relaxants (dantrium),4 nonsteroidal orally active an-
tiandrogens (nilutamide),5 orally active aldose reductase in-
hibitors (sorbinil),6 and antibacterial drugs (nitrofuranto-
in).7 A hydantoin-based compound, RU58841, has been de-
veloped as a promising antibaldness agent.8 Moreover,
several new potential therapeutic options have also recent-
ly emerged for hydantoin-based molecules, including anti-
hypertensive,9 antiinflammatory,10 antidiabetic,11 antifun-
gal,12 antiviral,13 and antitussive activities14 or selective
cyclooxygenase-2 inhibition.15 Hydantoin moieties also
constitute the core structure of various natural products.16
Along with their use as chiral auxiliaries,17 hydantoins are
Substituted hydantoins can be synthesized by alkylation
or arylation of hydantoin at the N-3 position.20 There have
been many studies on the use of α-amino acids in the syn-
thesis of substituted hydantoins by cyclization of carba-
mate-protected amino amides,21 carbamate-protected di-
peptides,22 or ureido derivatives of amino acids or amino
esters.23–27 Among these methods, ureido derivatives have
been cyclized under base-24 or acid-catalyzed conditions.25
Ureido derivatives of amino esters have been synthesized
by the reaction of carbamate-protected amino esters with
amines,25 by reactions of amino esters isocyanates28 or N-
substituted carbamates,24,26,27 or by the reaction of amino
esters with amines in the presence of triphosgene.29 Fur-
thermore, both carbamate-protected amino esters and N-
substituted carbamates have been synthesized by using
chloroformates. However, all the above-mentioned
approaches are two-step processes and involve the use of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
D. K. Tanwar et al.
Letter
Synlett
hazardous, irritant, toxic, or moisture-sensitive reagents,
such as isocyanates or chloroformates. Although the syn-
thesis of substituted hydantoins has been carried out in
solution,30 on a solid support,31 and by the application of
mechanochemistry,32–34 the key reagents remain the same.
In 2014, Colacino and co-workers documented a mechano-
chemical preparation of 5-substituted and 5,5-disubstitut-
ed hydantoins by the reaction of amino ester hydrochlo-
rides with potassium cyanate (Scheme 1, Equation 1).32 In
2016, they again reported a mechanochemical preparation
of 3,5-disubstituted hydantoins from α-amino methyl es-
ters by using either 1,1′-carbonyldiimidazole (CDI) or alkyl
isocyanates (Scheme 1, equation 2).33 More recently, they
optimized the mechanochemical preparation of highly
functionalized 3,5-disubstituted hydantoins from α-amino
methyl esters and CDI by applying liquid-assisted grinding
(LAG) in the presence of poly(ethylene glycol).34 Therefore,
α-amino acid esters represent a class of versatile synthetic
precursors, as these molecules provide both nucleophilic
and electrophilic sites. Additionally, carbamates, also
known as blocked isocyanates, have been used as a safer re-
placement for isocyanates and as convenient synthetic
building blocks.35 In our quest to develop benign synthetic
methods, we have recently developed a method for the syn-
thesis of N-substituted carbamates by the reaction of
amines with diphenyl carbonate in an aqueous–organic
medium at room temperature.36 In continuation of our
work on carbamates and their applications as intermediates
in organic synthesis, we report here a one-pot method for
the synthesis of 3-substituted, 5-substituted, or 3,5-disub-
stituted hydantoins through the cyclization of α-amino acid
esters with carbamates (Scheme 1, Equation 3). This pro-
cess avoids use of hazardous or toxic reagents, unlike the
reported two-step procedures.
We began by using methyl D,L-phenylalaninate hydro-
chloride (1a) and phenyl propylcarbamate (2a) as model
substrates to investigate the optimal reaction conditions for
the synthesis of 5-benzyl-3-propylimidazolidine-2,4-dione
(3a). Our initial examinations began with the use of various
solvents and bases, but the desired 3,5-disubstituted hy-
dantoin (3a) was obtained in a low yield (Table 1, entries 1–
12). The major product of the reaction was identified as
methyl 3-phenyl-2-(3-propylureido)propanoate. We there-
fore concluded that the reaction proceeds through the for-
mation of an ureido derivative that then cyclizes to give the
hydantoin. Although the hydantoin was formed under all
reaction conditions, the highest yield was obtained when
triethylamine was used as a base in acetonitrile. To promote
the cyclization, various ratios of triethylamine and acetoni-
trile were explored, but again the desired product was al-
ways obtained in a low yield (entries 13–15). The highest
yield was obtained when a 2:1 mixture of acetonitrile and
Et3N was used. The use of triethylamine alone as a solvent
reduced the yield, possibly due to the insolubility of the re-
Previous works
O
R2
(eq 1)
R1 R2
O
R1
R1 R2
KOCN, H2O
Ball-milling
KOH
NH
OMe
HN
OMe
H2N
N
Ball-milling
HCl⋅H2N
H
O
O
O
(eq 2)
O
R1
R2
N
C
O
R2
OMe
N
N
Ball-milling
H
H
R1
O
Ureido derivative
OMe
HCl⋅H2N
O
R1
O
OMe
CDI
N
N
N
H
Ball-milling
R2 NH2
O
N-Carbamoylimidazole-activated amino ester
O
R1
Present work
(eq 3)
N
R2
HN
R1
O
OMe
HCl⋅H2N
O
R1
HN
O
R1
O
NaOH
reflux
MeCN–Et3N
reflux
R2
N
R2
OMe
N
N
H
H
H
O
PhO
N
R2
O
Ureido derivative
O
Scheme 1 Synthesis of substituted hydantoins
actants and products in triethylamine (entry 16). Taking
our inspiration from a report in the literature,27 we used in-
organic bases such as Na2CO3 and NaOH in an attempt to cy-
clize the intermediate ureido derivative in a 2:1 mixture of
acetonitrile and triethylamine; the base was added ten
hours after the start of the reaction (entries 17 and 18).
Similar yields were obtained in both cases, but the reaction
in the presence of NaOH was complete in less time com-
pared with the reaction in the presence of Na2CO3. These re-
actions were also performed by using various molar ratios
of carbamate, and the highest yield was obtained when 1.1
equivalents of carbamate were used. Further increases in
the molar ratio had no significant effects on outcome of the
reaction.
With the optimal reaction conditions in hand,37 we ex-
amined the reactions of a range of α-amino methyl esters
1a–d with N-substituted carbamates 2a–l to give the corre-
sponding 3,5-disubstituted hydantoins 3a–s (Figure 2).
The reactions proceeded smoothly, except that of phe-
nyl isopropylcarbamate (2d) with methyl phenylalaninate
hydrochloride (1a), which gave only the ureido derivative,
and no cyclization was observed (Scheme 2). This probably
results from steric hindrance around the nitrogen atom,
rendering it less nucleophilic. A similar outcome has been
reported by Konnert and co-workers.33
With this exception, the reactions of other N-substitut-
ed carbamates with various α-amino acid esters produced
3,5-disubstituted hydantoins 3a–s in moderate to good
yields (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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D. K. Tanwar et al.
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Synlett
Table 1 Optimization of the Reaction Conditions for the Synthesis of a
3,5-Disubstituted Hydantoina
O
O
O
O
O
O
O
O
NH2⋅HCl
NH2⋅HCl
NH2⋅HCl
NH2⋅HCl
O
H
O
O
N
1c
1d
1b
1a
O
N
H
N
H
N
O
H
N
HN
NH2⋅HCl
O
O
O
O
1a
2a
O
O
O
3a
2b
2c
2a
H
H
H
Entry Reaction conditions
Yieldb (%)
O
N
O
N
O
N
O
O
1
CH2Cl2, Na2CO3 (5 equiv), reflux, 24 h
CH2Cl2, NaOH (5 equiv), reflux, 24 h
CH2Cl2, Et3N (5 equiv), reflux, 24 h
CH2Cl2, pyridine (5 equiv), reflux, 24 h
CH2Cl2, DMAP (5 equiv), reflux, 24 h
MeCN, Na2CO3 (5 equiv), reflux, 24 h
MeCN, NaOH (5 equiv), reflux, 24 h
MeCN, Et3N (5 equiv), reflux, 24 h
MeCN, pyridine (5 equiv), reflux, 24 h
MeCN, DMAP (5 equiv), reflux, 24 h
THF, Et3N (5 equiv), reflux, 24 h
THF, DMAP (5 equiv), reflux, 24 h
MeCN– Et3N (1:1), reflux, 24 h
MeCN–Et3N (1:2), reflux, 24 h
28
25
30
27
21
25
25
32
28
23
20
20
40
40
45
30
O
2e
2d
2f
2
H
H
N
O
N
O
3
4
O
O
2h
2g
5
H
H
O
N
6
O
O
N
7
O
2i
2j
8
9
H
H
N
O
N
O
10
11
12
13
14
15
16
17
O
O
2l
2k
Figure 2 Diverse α-amino methyl esters 1a–d and N-substituted carba-
mate 2a–l employed in the synthesis of 3,5-disubstituted hydantoins 3a–s
MeCN– Et3N (2:1), reflux, 24 h
Et3N, reflux, 24 h
O
O
H
O
N
i) MeCN–Et3N
(2:1), reflux, 10 h
R2
N
R2
O
HN
O
MeCN–Et3N (2:1), reflux, 10 h, then Na2CO3 (2.5 equiv), 75
reflux, 12 h
NH2⋅HCl
ii) NaOH (2.5 equiv), reflux, 8 h
O
2
1e
3
18
MeCN–Et3N (2:1), reflux, 10 h, then NaOH (2.5 equiv),
reflux, 8 h
75
O
O
a Reaction conditions: 1a (1 mmol), 2a (1.1 mmol).
N
b Isolated yield.
N
HN
HN
O
O
3t (67%)
from 1e and 2k
3u (74%)
from 1e and 2l
O
O
Scheme 4 Synthesis of 3-substituted hydantoins. Reaction conditions:
glycine methyl ester hydrochloride (1e; 2 mmol), N-substituted carba-
mate 2 (2.2 mmol), MeCN (12 mL), Et3N (6 mL), NaOH (5 mmol).
NH2⋅HCl
i) MeCN–Et3N
(2:1), reflux, 10 h
O
H
ii) NaOH (2.5 equiv), reflux, 8 h
O
O
N
N
N
H
H
O
O
Ureido derivative
methyl ester hydrochloride (1e) with N-substituted carba-
mates 2 also proceeded smoothly and gave the expected
products 3t and 3u in good yields (Scheme 4).
Scheme 2 Reaction of phenyl isopropylcarbamate 2d with methyl
phenylalaninate hydrochloride
We explored the scope and limitations of this method-
ology further by synthesizing 5-substituted hydantoins
from commercially available unsubstituted phenyl carba-
mate (2m). The reaction of phenyl carbamate (2m) with α-
amino methyl esters 1a and 1d gave 5-substituted hydan-
toins 3v and 3w, respectively, in good yields (Scheme 5).
After successfully synthesizing 3,5-disubstituted hydan-
toins, we attempted to synthesize 3-substituted hydantoins
by the reaction of glycine methyl ester hydrochloride (1e)
with N-substituted carbamates. The reaction of glycine
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D. K. Tanwar et al.
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O
O
H
O
O
R1
HN
O
N
i) MeCN–Et3N
(2:1), reflux, 10 h
R1
HN
R1
R2
i) MeCN–Et3N
(2:1), reflux, 10 h
O
NH2
R1
O
N
R2
NH
O
O
NH2.HCl
ii) NaOH (2.5 equiv), reflux, 8 h
O
O
NH2⋅HCl
ii) NaOH (2.5 equiv), reflux, 8 h
O
1
O
2
1
2m
3
3
O
O
O
N
O
NH
O
NH
HN
HN
N
N
N
O
O
HN
HN
HN
HN
3v (73%)
3w (73%)
from 1d and 2m
O
O
O
from 1a and 2m
O
3d (68%)
from 1a and 2e
3b (76%)
from 1a and 2b
3c (74%)
from 1a and 2c
3a (75%)
from 1a and 2a
Scheme 5 Synthesis of 5-substituted hydantoins. Reaction conditions:
α-amino methyl ester 1 (2 mmol), phenyl carbamate (2m; 2.2 mmol),
MeCN (12 mL), Et3N (6 mL), NaOH (5 mmol).
O
O
O
O
N
N
N
HN
HN
HN
O
O
O
O
NH2⋅HCl
3g (77%)
from 1a and 2h
3f (74%)
from 1a and 2g
2.017 g
O
3e (73%)
from 1a and 2f
i) MeCN–Et3N
(2:1), reflux, 10 h
N
ii) NaOH (2.5 equiv), reflux, 8 h
HN
H
O
N
O
O
O
O
1.595 g (78%)
O
1.817 g
N
N
N
HN
HN
HN
Scheme 6 Gram-scale synthesis of ethotoin
O
O
O
3j (73%)
from 1a and 2k
3h (65%)
from 1a and 2i
3i (71%)
from 1a and 2j
To demonstrate further the practicality of the method
described above, we synthesized the antiepileptic drug
ethotoin on a gram scale, and obtained the desired product
in 78% isolated yield (Scheme 6).38
In conclusion, an efficient, cost-effective, and practical
method has been developed for the preparation of 3-substi-
tuted, 5-substituted, and 3,5-disubstituted hydantoins
without the use of hazardous, irritant, toxic, or moisture-
sensitive reagents such as isocyanates or chloroformates.
This efficient procedure has a broad substrate scope and
consistently gives substituted hydantoins in good to excel-
lent yields under mild reaction conditions.
O
O
N
O
N
N
HN
HN
HN
O
O
O
3l (71%)
from 1b and 2k
3m (72%)
from 1b and 2l
3k (74%)
from 1a and 2l
O
N
O
O
N
N
HN
HN
HN
O
O
O
3p (72%)
from 1d and 2b
3n (73%)
from 1c and 2k
3o (70%)
from 1c and 2l
O
O
O
Acknowledgment
N
N
N
HN
HN
This study was supported by the National Institute of Pharmaceutical
Education and Research, S.A.S. Nagar, Punjab (INDIA). D.K.T. thanks
the University Grants Commission (UGC), New Delhi (India) for the
award of a scholarship for doctoral studies.
HN
O
O
O
3r (72%)
from 1d and 2k
3s (73%)
from 1d and 2l
3q (75%)
from 1d and 2c
Scheme 3 Synthesis of 3,5-disubstituted hydantoins. Reaction condi-
tions: α-amino methyl ester 1 (2 mmol), N-substituted carbamate 2
(2.2 mmol), MeCN (12 mL), Et3N (6 mL), NaOH (5 mmol).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588468.
S
u
p
p
o
nrtogI
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S
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p
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(37) Substituted Hydantoins 3a–w; General Procedure
The appropriate methyl α-amino ester hydrochloride 1 (2
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of MeCN (12 mL) and Et3N (6 mL), and reaction mixture was
refluxed for 10 h. NaOH (5 mmol) was then added, and the reac-
tion was continued for another 8 h. When the reaction was
complete, the solvents were distilled off and the residue was
partitioned between EtOAc (70 mL) and 0.1 M aq HCl (20 mL).
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
D. K. Tanwar et al.
Letter
Synlett
The organic layer was washed with brine, dried (Na2SO4), fil-
tered, and concentrated to give a crude product that was puri-
fied by either crystallization (hexane–EtOAc) or by column
chromatography (silica gel, hexane–EtOAc).
DMSO-d6): δ = 10.44 (br s, 1 H), 7.92 (br s, 1 H), 7.29–7.17 (m, 5
H), 4.33 (t, J = 4.8 Hz, 1 H), 2.97–2.88 (m, 2 H). 13C NMR (100
MHz, DMSO-d6): δ = 175.7, 157.6, 136.0, 130.2, 128.5, 127.1,
58.8, 36.8. HRMS (ESI): m/z Calcd [M + Na]+ for C10H10N2NaO2:
213.0640; found: 213.0637.
5-Benzyl-3-propylimidazolidine-2,4-dione (3a)
This compound was prepared by the general procedure, and
purified by crystallization (hexane–EtOAc) to give a white solid;
yield: 0.350 g (75%); mp 147–149 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 8.21 (br s, 1 H), 7.25–7.13 (m, 5 H), 4.35 (t, J = 4.4
Hz, 1 H), 3.17–3.00 (m, 2 H), 2.96 (d, J = 4.5 Hz, 2 H), 1.24–1.10
(m, 2 H), 0.50 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, DMSO-d6):
δ = 174.0, 157.1, 135.3, 130.2, 128.4, 127.2, 57.3, 39.4, 36.5,
21.0, 11.1. HRMS (ESI): m/z Calcd [M + Na]+ for C13H16N2NaO2:
255.1109; found: 255.1102.
(38) Gram-Scale Synthesis of Ethotoin (3-Ethyl-5-phenylimidazo-
lidine-2,4-dione; 3q)
Methyl phenylglycinate hydrochloride (10 mmol, 2.017 g) and
phenyl ethylcarbamate (11 mmol, 1.817 g) were dissolved in a
mixture of MeCN (60 mL) and Et3N (30 mL), and the mixture
was refluxed for 10 h. NaOH (25 mmol, 1.0 g) was then added
and reaction was continued for another 8 h. When the reaction
was complete, the solvents were distilled off and the residue
was partitioned between EtOAc (350 mL) and 0.1 M aq HCl (100
mL). The organic layer was washed with brine (2 × 100 mL),
dried (Na2SO4), filtered, and concentrated to give the crude
product, which was purified by column chromatography [silica
gel, hexane–EtOAc (28%)] to give a white solid; yield: 1.595 g
(78%); mp 85–87 °C; 1H NMR (400 MHz, DMSO-d6): δ = 8.70 (br
s, 1 H), 7.43–7.31 (m, 5 H), 5.20 (s, 1 H), 3.43 (q, J = 3.7 Hz, 2 H),
1.08 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-d6):
δ = 172.8, 157.2, 136.2, 129.1, 128.8, 127.2, 60.2, 33.2, 13.7.
HRMS (ESI): m/z Calcd [M + Na]+ for C11H12N2NaO2: 227.0796;
found: 227.0782.
3-Benzylimidazolidine-2,4-dione (3t)
Purified by crystallization from hexane–EtOAc as white solid;
yield: 255 mg (67%); mp 140–142 °C. 1H NMR (400 MHz,
DMSO-d6): δ = 8.12 (br s, 1 H), 7.35–7.26 (m, 5 H), 4.53 (s, 2 H),
3.98 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ = 172.4, 157.8,
137.2, 128.9, 127.9, 127.8, 46.4, 41.4. HRMS (ESI): m/z Calcd [M
+ Na]+ for C10H10N2NaO2: 213.0640; found: 213.0625.
5-Benzylimidazolidine-2,4-dione (3v)
Purified by crystallization from hexane–EtOAc as white solid;
yield: 278 mg (73%); mp 187–189 °C; 1H NMR (400 MHz,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F